Fig. 7

Cell-intrinsic and cell-extrinsic etiologies converge on the epigenome to shape super-enhancer formation in cancer. The roles of genomic alterations, including somatic mutations in cancer drivers and non-coding regions, subsequent oncogenic signaling, as well as focal amplification are well-described mechanisms of super-enhancer activation in cancer. The earliest descriptions of cell-extrinsic enhancer reprogramming were in androgen- and estrogen-dependent cancers, where these hormones would signal to the nucleus. Recently, broader cell-extrinsic etiologies, including super-enhancer reprogramming by inflammation within the local tumor microenvironment and in response to targeted therapies to mediate resistance, have been increasingly described